cGVHD
Conditions
Brief summary
A single-center, Phase 1, open-label, investigator-initiated clinical trial evaluating the safety, tolerability, and preliminary efficacy of sarilumab (anti-IL-6R) monotherapy as a rescue in adult patients with belumosudil-refractory chronic graft-versus-host disease (cGVHD).
Interventions
DRUGBelumosudil
Belumosudil (2-(3-(4-(1H-indazol-5-ylamino) quinazolin-2-yl) phenoxy)-N-isopropylacetamide-methane sulfonic acid salt), formerly also known as KD025, is an orally available Rho-associated protein kinase-2 (ROCK2) selective inhibitor. Belumosudil will be provided as 200 mg tablets.
DRUGSarilumab
Sarilumab is an interleukin-6 (IL-6) receptor antagonist FDA approved for treatment of: * Adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). * Adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper. Sarilumab will be provided as single-use 1.14 ml prefilled glass syringes containing 131.6 mg/mL (150 mg), 175 mg/mL (200 mg) of sarilumab
Sponsors
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Active cGVHD and currently receiving belumosudil with inadequate response (defined as disease progression at any time or failure to achieve at least a partial response after a minimum of 3 months of belumosudil therapy, and for whom the treating physician believes a new systemic therapy is required). 3. Persistent cGVHD manifestations and systemic therapy indicated. 4. Karnofsky Performance Score of ≥ 60. Laboratory Parameters: 5. Absolute neutrophil count ≥ 1.5 x 109/L 6. Platelet count ≥ 50 x 109/L 7. ALT and AST \< 1.5 × ULN 8. Total bilirubin ≤ 1.5 × ULN 9. Glomerular filtration rate (GFR) ≥ 30 ml/min/1.73m2 General Criteria: 10. Negative urine pregnancy test at screening for females of childbearing potential. 11. Sexually active females of childbearing potential must agree to use two accepted methods of contraception during treatment and for 3 months after their last dose. 12. Sexually active male subjects with female partners of childbearing potential must agree to use two accepted methods of contraception and refrain from sperm donation during treatment and for at least 3 months after their last dose. 14\. Ability to provide written informed consent (or consent from legally authorized representative). 15. Minimum weight of 63 kg
Exclusion criteria
1. Not on a stable systemic cGVHD treatments for at least 2 weeks prior to screening. (Note: Concomitant corticosteroids, calcineurin inhibitors, sirolimus are allowed. Systemic investigational GVHD treatments are not permitted). 2. Histological relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening. 3. Current treatment with ibrutinib or ruxolitinib. Prior treatment is allowed with a washout of at least 1 week prior to randomization. General Criteria: 4. Pregnant or breastfeeding. 5. History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the sponsor-investigator, unsuitable for the study (such as malabsorption syndromes, poorly controlled psychiatric disease or coronary artery disease). 6. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) or history of human immunodeficiency virus (HIV). 7. Malignancy diagnosed within 3 years (other than malignancy for which transplant was performed), with the exception of: 1. Completely resected basal cell or squamous cell carcinoma of the skin 2. Carcinoma in situ of the cervix 3. Resected breast ductal carcinoma in situ 4. Prostate cancer with Gleason score \<6 and stable PSA over 12 months 8. QTc(F) \> 480 ms 9. Sponsor-investigator deems subject unlikely to adhere to study procedures/treatment. 10. Investigational agent, device, or procedure within 28 days of first dose (or 5 half-lives, whichever longer). 11. Active TB or a history of incompletely treated TB regardless of screening Quantiferon Result.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment-emergent adverse events | From first dose through 6 months after treatment initiation | To evaluate the safety and tolerability of sarilumab monotherapy for the treatment of cGVHD after inadequate response to Belumosudil. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Sarilumab | Baseline through 6 months | Maximum observed plasma concentration of sarilumab following administration. |
| Time to Maximum Plasma Concentration (Tmax) of Sarilumab | Baseline through 6 months | Time required to reach maximum plasma concentration following sarilumab administration. |
| Area Under the Plasma Concentration-Time Curve (AUC) of Sarilumab | Baseline through 6 months | Area under the plasma concentration-time curve used to characterize sarilumab exposure. |
| Incidence of serious infections | From first dose through 6 months | To evaluate the incidence of serious infections associated with sarilumab monotherapy as a rescue in subjects with belumosudil refractory cGVHD. |
| Overall response rate | Up to 6 months | To evaluate preliminary efficacy of sarilumab monotherapy as a rescue in subjects with cGVHD after inadequate response to belumosudil |
Contacts
CONTACTSally Arai, MD
PRINCIPAL_INVESTIGATORSally Arai, MD
Stanford Universiy
Outcome results
None listed